CN1876226A - Bilirubin adsorption material for treating hyperbilirubinemia - Google Patents
Bilirubin adsorption material for treating hyperbilirubinemia Download PDFInfo
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- CN1876226A CN1876226A CN 200610200096 CN200610200096A CN1876226A CN 1876226 A CN1876226 A CN 1876226A CN 200610200096 CN200610200096 CN 200610200096 CN 200610200096 A CN200610200096 A CN 200610200096A CN 1876226 A CN1876226 A CN 1876226A
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- BPYKTIZUTYGOLE-IFADSCNNSA-N Bilirubin Chemical compound N1C(=O)C(C)=C(C=C)\C1=C\C1=C(C)C(CCC(O)=O)=C(CC2=C(C(C)=C(\C=C/3C(=C(C=C)C(=O)N\3)C)N2)CCC(O)=O)N1 BPYKTIZUTYGOLE-IFADSCNNSA-N 0.000 title claims abstract description 166
- 239000000463 material Substances 0.000 title claims abstract description 69
- 238000001179 sorption measurement Methods 0.000 title claims abstract description 58
- 208000027119 bilirubin metabolic disease Diseases 0.000 title claims description 11
- 208000036796 hyperbilirubinemia Diseases 0.000 title claims description 11
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000004475 Arginine Substances 0.000 claims abstract description 16
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims abstract description 16
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000011543 agarose gel Substances 0.000 claims abstract description 4
- -1 aethanolamina Chemical compound 0.000 claims abstract description 3
- 239000000499 gel Substances 0.000 claims description 43
- 125000000524 functional group Chemical group 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 210000002381 plasma Anatomy 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- XGIKILRODBEJIL-UHFFFAOYSA-N 1-(ethylamino)ethanol Chemical compound CCNC(C)O XGIKILRODBEJIL-UHFFFAOYSA-N 0.000 claims description 15
- 239000004472 Lysine Substances 0.000 claims description 15
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 15
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 12
- ZNZYKNKBJPZETN-WELNAUFTSA-N Dialdehyde 11678 Chemical compound N1C2=CC=CC=C2C2=C1[C@H](C[C@H](/C(=C/O)C(=O)OC)[C@@H](C=C)C=O)NCC2 ZNZYKNKBJPZETN-WELNAUFTSA-N 0.000 claims description 8
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 abstract 2
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 abstract 1
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- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 3
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- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
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- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 2
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- PSYGHMBJXWRQFD-UHFFFAOYSA-N 2-(2-sulfanylacetyl)oxyethyl 2-sulfanylacetate Chemical compound SCC(=O)OCCOC(=O)CS PSYGHMBJXWRQFD-UHFFFAOYSA-N 0.000 description 1
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- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
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- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
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- External Artificial Organs (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Abstract
The related bilirubin adsorption material selects agarose gel as carrier activated by N, N'-carbonyldiimidazole, the dual-amido agent and dual-aldehydo agent as separation arm, and couples all of lycine, aethanolamina, arginine and n-butylamine on back end, wherein in 324mg/L blood, the adsorption capacity for former material with different coupled is: 0.71~1.21g/Lgel, 0.78~1.29g/Lgel, 0.91~1.44g/Lgel and 1.20~1.81g/Lgel, and the removal rate to bilirubin by material coupled n-butylamine is up to 50.0%. this invention has well adsorption rate with low cost.
Description
Technical field
The invention belongs to the bio-separation field of engineering technology.Relate to synthesized have lysine, the serial bilirubin adsorption material of ethylaminoethanol, arginine and n-butylamine adsorption function base, and in patient's blood plasma, carried out adsorption experiment.
Background technology
Bilirubin is the metabolite of ferroheme in the red blood cell aging, combines with glucuronic acid after further metabolism excretes at liver under the normal condition.If liver obstacle occurs to its metabolism, then the bilirubin concentration in the blood can raise, and will produce jaundice when bilirubin concentration surpasses 17 μ mol/L,
The bilirubin of this moment becomes a kind of endogenous toxin again, and very permeable is crossed biomembrane, and combines with nerve nucleus through blood-brain barrier, disturbs the eubolism and the function of brain cell, and brain is produced irreversible toxic and side effect.Bilirubin encephalopathy easily betides the neonate, and often causes death.Biliary obstruction, acute and chronic icterepatitis, toxic hepatitis, various hemolytic hepatitis, icterus neonatorum disease etc. all can cause liver to bilirubinic metabolic disorder, thereby cause bilirubinic accumulation in patient's body, produce hyperbilirubinemia, bilirubin concentration in their body can cause the patient physiological imbalance up to nearly 700 μ mol/L.Current, the death rate that acute liver failure causes is up to 80%.If can remove bilirubin excessive in the blood timely, with great mitigate the disease, carry out self-regeneration for the patient liver cell and liver transfer operation is raced against time, the life of saving patient is significant.
Studies show that in a large number, utilize blood purification absorption therapy can treat hyperbilirubinemia effectively.The key of this therapy is the performance of bilirubin adsorption material.Over nearly 20 years, the research of bilirubin adsorption material mainly concentrates on carrier and functional group two aspects, type according to carrier can be divided into synthetic resin adsorbent and polysaccharide adsorbent, can be divided into wide spectrum class adsorbent and affinity adsorbent according to the type of functional group.
The synthetic resin adsorbent is cancellated high molecular polymer, can carry out manually synthesizing according to different needs, makes it possess specific absorption property, is to study more adsorbent at present.The resinae adsorbent can be divided into ion exchange resin and polymeric adsorbent two big classes.A) use the ion exchange resin type bilirubin adsorption material and remove the bilirubinic example BL-300 anion exchange resin type bilirubin adsorption material that to have with the rare basic benzene copolymer of second be skeleton, the commercialization of this type of sorbing material.In actual therapeutic, such sorbing material can reach 50 ~ 60% to the clearance of patient's blood plasma mesobilirubin, but treatment time is longer, generally needs 4 ~ 6 hours.In addition, and the costing an arm and a leg of this type of sorbing material (6000 ~ 9000RMB), be difficult to be accepted by vast hyperbilirubinemia patient.B) use polymeric adsorbent type bilirubin adsorption material and remove the beta-cyclodextrin cross-linked polymer microballoon (China Patent No. ZL 03111583.7) etc. that bilirubinic example has macromolecule resin type adsorbent for bilirubin (China Patent No. ZL 200410016088.2), adsorbing bilirubin.Macromolecule resin type adsorbent for bilirubin (China Patent No. ZL 200410016088.2) is to be carrier with the polystyrene-divinylbenzene, and beta cyclodextrin is the functional group adsorbing bilirubin.The animal's whole blood perfusion experiment shows: this sorbing material can reach 61.2% to bilirubinic clearance, but does not provide more detailed experiments result.The beta-cyclodextrin cross-linked polymer microballoon of adsorbing bilirubin (China Patent No. ZL 03111583.7) is to be crosslinking agent with the vulcabond, forms with the cyclodextrin monomer condensation.Experimental result shows: such sorbing material is not containing the bovine serum albumin(BSA) bilirubin solution and is containing in the bovine serum albumin(BSA) bilirubin solution bilirubinic clearance is respectively 87.5% and 51.5%.As seen the albumin molecule is serious to adsorption effect influence, and do not investigate in the patent sorbing material in actual plasma to bilirubinic absorption property, and the sorbing material that only in actual plasma bilirubin is had a good adsorption properties just has clinical meaning.
The adsorbent that material surface functional group and bilirubin have affinity interaction is called as affinity adsorbent, with human serum albumins (China Patent No. ZL 01128196.0) and triasine dyes (Denizli A etc., Journal of Chromatography B:Biomedical Sciences and Applications, 1998,707 (1-2): 25-31) all belong to this type of for the adsorbent of functional group.The immune absorption material (China Patent No. ZL 01128196.0) that is used for the treatment of hyperbilirubinemia is to be carrier with the Ago-Gel, and human serum albumin HSA is the functional molecular of adsorbing bilirubin.Though this type of sorbing material blood compatibility is good, in blood plasma bilirubinic clearance is reached 57.3%.But terminal coupling human serum albumin HSA is the aglucon adsorbing bilirubin, makes preparation cost higher, and the use of human serum albumin HSA makes that also sorbing material is easily polluted by Institute of Micro-biology, the difficult preservation.With the triasine dyes is the adsorbent for bilirubin of functional group, is carrier with the copolymer of GDMA and methacrylic acid-2-hydroxy methacrylate.This type of sorbing material can reach 24.2mg/g to bilirubinic adsorbance, but the problem of coming off of dyestuff aglucon makes such sorbing material be difficult to be applied to clinical.
At present, the rare basic benzene copolymer resin anion (R.A.) of second that has only Japan to produce has obtained application clinically, and other adsorbent also has very big distance from clinical practice.Studying novel adsorbent for bilirubin solves in (1) patient's blood plasma system that present bilirubin adsorption material exists low to bilirubinic adsorption capacity; (2) poor, the defective such as cost an arm and a leg of blood compatibility is significant to the life of saving the serious hepatitis patient.
We have proposed with natural polysaccharide material is carrier, improving sorbing material to bilirubinic adsorption capacity, final synthetic to blood mesobilirubin clearance height, sorbing material that blood compatibility is good by screening function group chain.Overall conception is: (1) selects the polysaccharide material Ago-Gel is that carrier is to strengthen blood compatibility.(2) in view of spacerarm and terminal functional group bilirubinic absorption all there is contribution, calculate the whole functional group chain of sorbing material and the hydrophobicity constant of bilirubin molecule by computer software, according to " similar mixing " principle, supposition and the immediate sorbing material of bilirubin molecule hydrophobicity constant are to bilirubinic absorption property optimum.
Summary of the invention
The objective of the invention is to design, synthetic a kind of nontoxic, harmless, bilirubin advantages of good adsorption effect, glycan sorbing material that cost is low, the sorbing material that mainly exists in the prior art is low to the bilirubin adsorption capacity in actual patient blood plasma, defective such as cost an arm and a leg to overcome.Reach removal, and have the purpose of good blood compatibility the bilirubin high selectivity.
Technical scheme of the present invention is as follows:
(1) selecting the good Ago-Gel of blood compatibility for use is carrier, and it is the polysaccharose substance that extracts from natural plants, contains a large amount of hydroxyls.Generally, it is an inertia, does not have adsorptivity, so blood compatibility is good.Use N, N ' carbonyl dimidazoles activated carrier, with two amino reagent, dialdehyde base reagent as the spacerarm molecule, according to mechanism of action such as the hydrogen bond that may exist between sorbing material and the bilirubin molecule, hydrophobic, ionic bonds, several different terminal functional groups of bonding (lysine, ethylaminoethanol, arginine and n-butylamine) synthesize a series of bilirubin adsorption materials.
(2) optimize the minimum energy configuration of sorbing material by computer software, and the hydrophobicity constant of whole functional group chain when calculating this configuration, by with the sorbing material that relatively comes to determine absorption property the best of bilirubin molecule hydrophobicity constant.It is generally acknowledged that the sorbing material more approaching with bilirubin molecule hydrophobicity constant has absorption property preferably, this is because according to " similar mixing " principle, and the adsorption of itself and bilirubin molecule should be stronger.
According to above-mentioned experiment design, the invention provides out the bilirubin absorption that is used for the treatment of hyperbilirubinemia
Material, comprise that selecting Ago-Gel for use is carrier, adopt N, N ' carbonyl dimidazoles activated carrier, with two amino reagent, dialdehyde base reagent as the spacerarm molecule, the a series of of terminal coupling lysine, ethylaminoethanol, arginine and n-butylamine respectively have building-up process than the glycan sorbing material of high-adsorption-capacity to bilirubin, it is characterized in that:
1) utilizes N, N ' carbonyl dimidazoles activated agarose gel, N wherein, the mass concentration of N ' carbonyl dimidazoles is 60 ~ 220g/L, the percent by volume of Ago-Gel in solution is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 1 ~ 2 hour reaction time, the active group density on Ago-Gel surface, reaction back is 72 ~ 192mmol/Lgel;
2) utilize the synthetic Ago-Gel that has the amino functional group of two amino reagent.The wherein two percents by volume of amino reagent in solution are 2 ~ 20%, N, the percent by volume of Ago-Gel in solution of N ' carbonyl dimidazoles activation is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 2 ~ 4 hours reaction time, the amino density on Ago-Gel surface, reaction back is 50 ~ 107mmol/Lgel;
3) utilize the synthetic Ago-Gel that has the aldehyde radical functional group of dialdehyde base reagent.Wherein the percent by volume of dialdehyde base reagent in solution is 3 ~ 25%, the percent by volume of Ago-Gel in solution that has the amino functional group is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 2 ~ 18 hours reaction time, the aldehyde radical density on Ago-Gel surface, reaction back is 13 ~ 23mmol/Lgel;
4) utilize lysine, ethylaminoethanol, arginine and n-butylamine and have the Ago-Gel reaction of aldehyde radical functional group, the synthesizing series bilirubin adsorption material respectively.Wherein, lysine, ethylaminoethanol, arginine and the n-butylamine molar concentration in solution is respectively 0.2 ~ 1.0mol/L, the percent by volume of Ago-Gel in solution that has the aldehyde radical functional group is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 2 ~ 24 hours reaction time, the adsorption function base density on Ago-Gel surface, reaction back is 13 ~ 23mmol/Lgel;
5) with lysine, ethylaminoethanol, arginine and n-butylamine being the bilirubin adsorption material of terminal functional group, is that adsorption capacity in the human plasma of 324mg/L is respectively 0.71 ~ 1.21g/Lgel, 0.78 ~ 1.29g/Lgel, 0.91 ~ 1.44g/Lgel and 1.20 ~ 1.81g/Lgel at bilirubin concentration.Density be 23mmol/Lgel be the sorbing material of terminal functional group with n-butylamine, be that the bilirubin clearance in the actual patient blood plasma of 474 μ mol/L reaches 55.2% to bilirubin concentration.
Effect of the present invention and benefit are:
Selecting the polysaccharide material Ago-Gel for use is carrier, compares with other sorbing materials, has advantages such as blood compatibility is good, non-specific adsorption is little, has strengthened the security of treatment;
Adopting lysine, ethylaminoethanol, arginine and n-butylamine is terminal functional group, replaces human serum albumin HSA, guarantees result of treatment, reduces production costs, and makes material be easy to sterilization, transport and preserve.As density be 23mmol/Lgel be the sorbing material of terminal functional group with n-butylamine, be that bilirubin clearance in the actual patient blood plasma of 474 μ mol/L reaches absorption in 55.2%, 0.5 hour and reaches balance substantially to bilirubin concentration.The bilirubin clearance is near import adsorption column level, but adsorption efficiency is far above the import adsorption column.
Description of drawings
Accompanying drawing be with n-butylamine be the bilirubin adsorption material of terminal functional group in actual patient blood plasma to bilirubinic clearance and time relation figure.
Coordinate: abscissa is adsorption time, and unit is hour. Ordinate is bilirubinic clearance, and % represents with percentage. Symbol represents total bilirubin symbol zero and represents bilirubin direct, and symbol △ represents indirect bilirubin.
Experiment condition: density is the bilirubin adsorption material sorbing material take n-butylamine as terminal function base of 23mmol/Lgel 55ml (dress post), 2.5 hours Dynamic Adsorption time, the volume ratio that contains bilirubin patient blood plasma and sorbing material is 10: 1, courage The red pigment initial concentration is 474 μ mol/L.
The specific embodiment
Below in conjunction with technical scheme and accompanying drawing, be described in detail details most preferred embodiment of the present invention.
Embodiment 1:N, the preparation of N ' carbonyl dimidazoles activated agarose gel
Take by weighing Ago-Gel 0.43 ~ 1.0L, remove anticorrisive agent in the gel with deionized water for 4-5 time through vacuum filtration, clean gel with 30%, 70%, 100% acetone successively, take by weighing the N of 60 ~ 220g, N ' carbonyl dimidazoles is dissolved in the 1.0L acetone, then washed gel is added in this solution,, reacted in 150 rev/mins the shaking table 1 ~ 2 hour 25 ~ 37 ℃ of temperature.After reaction finishes, clean the gel that has activated repeatedly with the acetone of 6 ~ 10 times of volumes, vacuum filtration is removed the imidazoles that produces in the course of reaction.This moment, the active group density on Ago-Gel surface was 72 ~ 192mmol/Lgel.
Embodiment 2: the preparation of two amino reagent coupling Ago-Gels
After in 1.0L acetone, adding the two amino reagent (as diaminourea dipropyl imines, hexamethylene diamine, ethylenediamine etc.) of 0.021 ~ 0.25L, add 0.43 ~ 1.0L N again, the Ago-Gel that N ' carbonyl dimidazoles activates 25 ~ 37 ℃ of temperature, reacted in 150 rev/mins the shaking table 2 ~ 4 hours.After reaction finishes, with the deionized water of 6 ~ 10 times of volumes gel behind the cleaning reaction repeatedly, and then with the borate buffer cleaning glue sample of 0.15mol/L, pH8.2.This moment, the amino density on Ago-Gel surface was 50 ~ 107mmol/Lgel.
Embodiment 3: have the preparation of the Ago-Gel of aldehyde radical active group
The Ago-Gel of the two amino reagent of 0.43 ~ 1.0L coupling is dispersed in 1.0L to be contained in the borate buffer that dialdehyde base reagent (as glutaraldehyde, glyoxal etc.) percent by volume is 3 ~ 25% 0.15mol/L, pH8.2, at temperature 25 ~ 37 Fei, reacted in 150 rev/mins the shaking table 2 ~ 18 hours.After reaction finishes, use the deionized water of 6 ~ 10 times of volumes successively, the 2mol/L acetic acid of 6 ~ 10 times of volumes, the 0.15mol/L of 6 ~ 10 times of volumes, the borate buffer of pH8.2 clean the glue sample, drain.This moment, the aldehyde radical density on Ago-Gel surface was 13 ~ 23mmol/Lgel.
Embodiment 4: by the calculating screening function base of hydrophobicity constant
Utilizing computer software ChemOffice to calculate with lysine, ethylaminoethanol, arginine and n-butylamine is that the hydrophobicity constant of the sorbing material of terminal functional group is respectively-0.8441,-0.8607,-1.1197 and 0.8978, the hydrophobicity constant of bilirubin molecule is 1.0413.Be that the hydrophobicity constant (1.0413) of hydrophobicity constant (0.8978) and bilirubin molecule of bilirubin adsorption material of terminal functional group is the most approaching with n-butylamine in theory, according to " similar mixing " principle, infer that it should have higher adsorption capacity to bilirubin, the accuracy of supposition needs further to verify by adsorption experiment.
Embodiment 5: lysine, ethylaminoethanol, arginine and n-butylamine are the preparation and the evaluation of the sorbing material of terminal functional group
Respectively lysine, ethylaminoethanol, arginine and n-butylamine are dissolved in the borate buffer of 0.15mol/L, pH8.2 of 1.0L, making its molar concentration is 0.2 ~ 1.0mol/L, the Ago-Gel that 0.43 ~ 1.0L is had the aldehyde radical active group adds respectively wherein, at temperature 25 ~ 37 Fei, reacted in 150 rev/mins the shaking table 2 ~ 24 hours.After reaction finishes, with the washed with de-ionized water glue sample of 6 ~ 10 times of volumes, with the two keys that generate in the sodium borohydride reduction course of reaction.This moment, the adsorption function base density on Ago-Gel surface was 13 ~ 23mmol/Lgel.
Get the bilirubin adsorption material 0.5ml that contains the difference in functionality base respectively, add 5ml hyperbilirubinemia patient blood plasma, bilirubin concentration is 324mg/L, static absorption 2.5 hours, and the variable quantity of blood plasma mesobilirubin calculates the bilirubin adsorbance before and after the analysis absorption.Experimental result shows: with lysine, ethylaminoethanol, arginine and n-butylamine is the sorbing material of terminal functional group, and the adsorption capacity of human plasma mesobilirubin is respectively 0.71 ~ 1.21g/Lgel, 0.78 ~ 1.29g/Lgel, 0.91 ~ 1.44g/Lgel and 1.20 ~ 1.81g/Lgel.Be that the performance of the bilirubin adsorption material of terminal functional group is better than other sorbing material with n-butylamine wherein, this result coincide with theoretical result calculated to a certain extent.
Embodiment 6: the external dynamic adsorption experiment that with n-butylamine is the bilirubin adsorption material of terminal functional group
Getting with n-butylamine is the bilirubin adsorption material 55ml of terminal functional group (the internal diameter 4cm in the adsorption column that packs into, height 6cm), 550ml is suffered from hyperbilirubinemia patient's blood plasma and cross post circulation 2.5 hours, analyze the variable quantity of absorption front and back blood plasma mesobilirubin, calculate the bilirubin clearance.Experimental result shows: be the bilirubin adsorption material of terminal functional group with n-butylamine, be that total bilirubin clearance in the actual patient blood plasma of 474 Jing ol/L reaches 55.2% to bilirubin concentration, the clearance of bilirubin direct reaches 57.1%, the clearance of indirect bilirubin reaches 52.2%, and this effect is near import bilirubin adsorption column level.From accompanying drawing 1, it can also be seen that, sorbing material is in a basic balance to bilirubin absorption in 0.5 hour, because 4 ~ 6 hours ability of import bilirubin adsorption column reaches adsorption equilibrium substantially, this result can illustrate with n-butylamine be the bilirubin adsorption material of terminal functional group to bilirubinic adsorption rate far above import bilirubin adsorption column.
Claims (2)
1. bilirubin adsorption material that is used for the treatment of hyperbilirubinemia, comprise that selecting Ago-Gel for use is carrier, adopt N, N ' carbonyl dimidazoles activated carrier, with two amino reagent, dialdehyde base reagent as the spacerarm molecule, the a series of of terminal coupling lysine, ethylaminoethanol, arginine and n-butylamine respectively have synthetic method than the glycan sorbing material of high-adsorption-capacity to bilirubin, it is characterized in that:
A) utilize N, N ' carbonyl dimidazoles activated agarose gel, N wherein, the mass concentration of N ' carbonyl dimidazoles is 60 ~ 220g/L, the percent by volume of Ago-Gel in solution is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 1 ~ 2 hour reaction time, the active group density on Ago-Gel surface, reaction back is 72 ~ 192mmol/Lgel;
B) utilize the synthetic Ago-Gel that has the amino functional group of two amino reagent, the wherein two percents by volume of amino reagent in solution are 2 ~ 20%, N, the percent by volume of Ago-Gel in solution of N ' carbonyl dimidazoles activation is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 2 ~ 4 hours reaction time, the amino density on Ago-Gel surface, reaction back is 50 ~ 107mmol/Lgel;
C) utilize the synthetic Ago-Gel that has the aldehyde radical functional group of dialdehyde base reagent, wherein the percent by volume of dialdehyde base reagent in solution is 3 ~ 25%, the percent by volume of Ago-Gel in solution that has the amino functional group is 30 ~ 50%, 25 ~ 37 ℃ of reaction temperatures, in 2 ~ 18 hours reaction time, the aldehyde radical density on Ago-Gel surface, reaction back is 13 ~ 23mmol/Lgel;
D) utilize lysine, ethylaminoethanol, arginine and n-butylamine and have the Ago-Gel reaction of aldehyde radical functional group respectively, the synthesizing series bilirubin adsorption material, wherein, lysine, ethylaminoethanol, arginine and the n-butylamine molar concentration in solution is respectively 0.2 ~ 1.0mol/L, the percent by volume of Ago-Gel in solution that has the aldehyde radical functional group is 30 ~ 50%, reaction temperature 25 ~ 37? in 2 ~ 24 hours reaction time, the adsorption function base density on Ago-Gel surface, reaction back is 13 ~ 23mmol/Lgel.
2. a kind of bilirubin adsorption material that is used for the treatment of hyperbilirubinemia according to claim 1, its feature also is: with lysine, ethylaminoethanol, arginine and n-butylamine is the bilirubin adsorption material of terminal functional group, is that adsorption capacity in the human plasma of 324mg/L is respectively 0.71 ~ 1.21g/Lgel, 0.78 ~ 1.29g/Lgel, 0.91 ~ 1.44g/Lgel and 1.20 ~ 1.81g/Lgel at bilirubin concentration.Density be 23mmol/Lgel be the sorbing material of terminal functional group with n-butylamine, be that the bilirubin clearance in the actual patient blood plasma of 474 μ mol/L reaches 55.2% to bilirubin concentration.
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